About six months ago, the parents of this 1-year-old boy first noticed the lesion on his shoulder. It started as a pinpoint papule but has grown to its current size—at which point, it caught their full attention. Although there are no associated symptoms, the parents request referral to dermatology to clear up the matter.

The child is reportedly healthy in all other respects, maintaining weight as expected, and normally active and reactive to verbal and visual stimuli.

EXAMINATION

A distinctive orangish brown, ovoid, 8 x 4–mm nodule is located on the child’s right superior shoulder. The lesion has a smooth, soft surface, and there is no tenderness on palpation. No additional lesions are seen elsewhere.

Eye examination reveals normal and symmetrical red reflexes.

What is the diagnosis?

Juvenile xanthogranuloma (JXG) is a rare, benign variant of non-Langerhans cell histiocytosis. This patient’s lesion is typical, but JXG can vary in appearance; some patients present with darker or larger lesions—or multiple lesions.

JXGs are essentially granulomatous tumors that, on histologic examination, display multinucleated giant cells called Touton giant cells. These macrophage-derived foam cells are seen in lesions with high lipid content.

JXG tends to favor the neck, face, and trunk but can appear around or (rarely) inside the eye, typically unilaterally in the iris. Benign in all other respects, ocular JXG lesions can cause spontaneous hyphema, glaucoma, or blindness; they must therefore be dealt with by a specialist. Fortunately, only about 10% of patients display ocular involvement.

JXGs can be confused with compound nevi, warts, or Spitz tumors. Therefore, biopsy is often necessary to establish the diagnosis.

TAKE-HOME LEARNING POINTS

• Juvenile xanthogranuloma (JXG) is a rare non-Langerhans cell tumor usually seen on the neck, face, or trunk of children younger than 2.
• The orangish brown, soft appearance of this patient’s papule was typical.
• Although atypical JXG lesions may require shave biopsy to confirm the diagnosis, they typically resolve on their own without treatment.
• When JXG lesions appear in the eye (most commonly in the iris), there is potential for serious complications, including heterochromia, glaucoma, spontaneous hyphema, or even blindness.

About six months ago, the parents of this 1-year-old boy first noticed the lesion on his shoulder. It started as a pinpoint papule but has grown to its current size—at which point, it caught their full attention. Although there are no associated symptoms, the parents request referral to dermatology to clear up the matter.

The child is reportedly healthy in all other respects, maintaining weight as expected, and normally active and reactive to verbal and visual stimuli.

EXAMINATION

A distinctive orangish brown, ovoid, 8 x 4–mm nodule is located on the child’s right superior shoulder. The lesion has a smooth, soft surface, and there is no tenderness on palpation. No additional lesions are seen elsewhere.

Eye examination reveals normal and symmetrical red reflexes.

What is the diagnosis?

Juvenile xanthogranuloma (JXG) is a rare, benign variant of non-Langerhans cell histiocytosis. This patient’s lesion is typical, but JXG can vary in appearance; some patients present with darker or larger lesions—or multiple lesions.

JXGs are essentially granulomatous tumors that, on histologic examination, display multinucleated giant cells called Touton giant cells. These macrophage-derived foam cells are seen in lesions with high lipid content.

JXG tends to favor the neck, face, and trunk but can appear around or (rarely) inside the eye, typically unilaterally in the iris. Benign in all other respects, ocular JXG lesions can cause spontaneous hyphema, glaucoma, or blindness; they must therefore be dealt with by a specialist. Fortunately, only about 10% of patients display ocular involvement.

JXGs can be confused with compound nevi, warts, or Spitz tumors. Therefore, biopsy is often necessary to establish the diagnosis.

TAKE-HOME LEARNING POINTS

• Juvenile xanthogranuloma (JXG) is a rare non-Langerhans cell tumor usually seen on the neck, face, or trunk of children younger than 2.
• The orangish brown, soft appearance of this patient’s papule was typical.
• Although atypical JXG lesions may require shave biopsy to confirm the diagnosis, they typically resolve on their own without treatment.
• When JXG lesions appear in the eye (most commonly in the iris), there is potential for serious complications, including heterochromia, glaucoma, spontaneous hyphema, or even blindness.

About six months ago, the parents of this 1-year-old boy first noticed the lesion on his shoulder. It started as a pinpoint papule but has grown to its current size—at which point, it caught their full attention. Although there are no associated symptoms, the parents request referral to dermatology to clear up the matter.

The child is reportedly healthy in all other respects, maintaining weight as expected, and normally active and reactive to verbal and visual stimuli.

EXAMINATION

A distinctive orangish brown, ovoid, 8 x 4–mm nodule is located on the child’s right superior shoulder. The lesion has a smooth, soft surface, and there is no tenderness on palpation. No additional lesions are seen elsewhere.

Eye examination reveals normal and symmetrical red reflexes.

What is the diagnosis?

Juvenile xanthogranuloma (JXG) is a rare, benign variant of non-Langerhans cell histiocytosis. This patient’s lesion is typical, but JXG can vary in appearance; some patients present with darker or larger lesions—or multiple lesions.

JXGs are essentially granulomatous tumors that, on histologic examination, display multinucleated giant cells called Touton giant cells. These macrophage-derived foam cells are seen in lesions with high lipid content.

JXG tends to favor the neck, face, and trunk but can appear around or (rarely) inside the eye, typically unilaterally in the iris. Benign in all other respects, ocular JXG lesions can cause spontaneous hyphema, glaucoma, or blindness; they must therefore be dealt with by a specialist. Fortunately, only about 10% of patients display ocular involvement.

JXGs can be confused with compound nevi, warts, or Spitz tumors. Therefore, biopsy is often necessary to establish the diagnosis.

TAKE-HOME LEARNING POINTS

• Juvenile xanthogranuloma (JXG) is a rare non-Langerhans cell tumor usually seen on the neck, face, or trunk of children younger than 2.
• The orangish brown, soft appearance of this patient’s papule was typical.
• Although atypical JXG lesions may require shave biopsy to confirm the diagnosis, they typically resolve on their own without treatment.
• When JXG lesions appear in the eye (most commonly in the iris), there is potential for serious complications, including heterochromia, glaucoma, spontaneous hyphema, or even blindness.

Tobacco use among middle and high school students has dropped since 2011, and e-cigarettes have replaced cigarettes as their favorite form of tobacco, according to the Centers for Disease Control and Prevention.

The prevalence of current tobacco use – defined as use on 1 or more days in the past 30 days – among high schoolers fell from 24.2% in 2011 to 19.6% in 2017, and middle school use decreased from 7.5% to 5.6% over that same time. That means the number of youth tobacco users went from almost 4.6 million in 2011 to slightly more than 3.6 million in 2017, Teresa W. Wang, PhD, and her associates said in the Morbidity and Mortality Weekly Report.

rfranki@mdedge.com

SOURCE: Wang TW et al. MMWR. 2018;67(22):629-33.

Tobacco use among middle and high school students has dropped since 2011, and e-cigarettes have replaced cigarettes as their favorite form of tobacco, according to the Centers for Disease Control and Prevention.

The prevalence of current tobacco use – defined as use on 1 or more days in the past 30 days – among high schoolers fell from 24.2% in 2011 to 19.6% in 2017, and middle school use decreased from 7.5% to 5.6% over that same time. That means the number of youth tobacco users went from almost 4.6 million in 2011 to slightly more than 3.6 million in 2017, Teresa W. Wang, PhD, and her associates said in the Morbidity and Mortality Weekly Report.

rfranki@mdedge.com

SOURCE: Wang TW et al. MMWR. 2018;67(22):629-33.

Tobacco use among middle and high school students has dropped since 2011, and e-cigarettes have replaced cigarettes as their favorite form of tobacco, according to the Centers for Disease Control and Prevention.

The prevalence of current tobacco use – defined as use on 1 or more days in the past 30 days – among high schoolers fell from 24.2% in 2011 to 19.6% in 2017, and middle school use decreased from 7.5% to 5.6% over that same time. That means the number of youth tobacco users went from almost 4.6 million in 2011 to slightly more than 3.6 million in 2017, Teresa W. Wang, PhD, and her associates said in the Morbidity and Mortality Weekly Report.

rfranki@mdedge.com

SOURCE: Wang TW et al. MMWR. 2018;67(22):629-33.

Federal officials will not block insurance companies from again using a workaround to cushion a steep rise in health premiums caused by President Donald Trump’s cancellation of a program established under the Affordable Care Act, Health and Human Services Secretary Alex Azar announced June 6.

The technique – called “silver loading” because it pushed price increases onto the silver-level plans in the ACA marketplaces – was used by many states for 2018 policies. But federal officials had hinted they might bar the practice next year.

At a hearing June 6 before the House Education and Workforce Committee, Mr. Azar said stopping this practice “would require regulations, which simply couldn’t be done in time for the 2019 plan period.”

States moved to silver loading after the president in October cut off federal reimbursement for so-called cost-sharing reduction subsidies that the ACA guaranteed to insurance companies. Those payments offset the cost of discounts that insurers are required by the law to provide to some low-income people to help cover their deductibles and other out-of-pocket costs.

States scrambled to let insurers raise rates so they would stay in the market. And many let them use this technique to recoup the lost funding by adding to the premium costs of midlevel silver plans in the health exchanges.

Because the formula for federal premium subsidies offered to people who purchase through the marketplaces is based on the prices of those silver plans, as those premiums rose so did the subsidies to help people afford them. That meant the federal government ended up paying much of the increase in prices.

At the committee hearing June 6, under questioning from Rep. Joe Courtney (D-Conn.), Mr. Azar declined to say if the department was considering a future ban.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Federal officials will not block insurance companies from again using a workaround to cushion a steep rise in health premiums caused by President Donald Trump’s cancellation of a program established under the Affordable Care Act, Health and Human Services Secretary Alex Azar announced June 6.

The technique – called “silver loading” because it pushed price increases onto the silver-level plans in the ACA marketplaces – was used by many states for 2018 policies. But federal officials had hinted they might bar the practice next year.

At a hearing June 6 before the House Education and Workforce Committee, Mr. Azar said stopping this practice “would require regulations, which simply couldn’t be done in time for the 2019 plan period.”

States moved to silver loading after the president in October cut off federal reimbursement for so-called cost-sharing reduction subsidies that the ACA guaranteed to insurance companies. Those payments offset the cost of discounts that insurers are required by the law to provide to some low-income people to help cover their deductibles and other out-of-pocket costs.

States scrambled to let insurers raise rates so they would stay in the market. And many let them use this technique to recoup the lost funding by adding to the premium costs of midlevel silver plans in the health exchanges.

Because the formula for federal premium subsidies offered to people who purchase through the marketplaces is based on the prices of those silver plans, as those premiums rose so did the subsidies to help people afford them. That meant the federal government ended up paying much of the increase in prices.

At the committee hearing June 6, under questioning from Rep. Joe Courtney (D-Conn.), Mr. Azar declined to say if the department was considering a future ban.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Federal officials will not block insurance companies from again using a workaround to cushion a steep rise in health premiums caused by President Donald Trump’s cancellation of a program established under the Affordable Care Act, Health and Human Services Secretary Alex Azar announced June 6.

The technique – called “silver loading” because it pushed price increases onto the silver-level plans in the ACA marketplaces – was used by many states for 2018 policies. But federal officials had hinted they might bar the practice next year.

At a hearing June 6 before the House Education and Workforce Committee, Mr. Azar said stopping this practice “would require regulations, which simply couldn’t be done in time for the 2019 plan period.”

States moved to silver loading after the president in October cut off federal reimbursement for so-called cost-sharing reduction subsidies that the ACA guaranteed to insurance companies. Those payments offset the cost of discounts that insurers are required by the law to provide to some low-income people to help cover their deductibles and other out-of-pocket costs.

States scrambled to let insurers raise rates so they would stay in the market. And many let them use this technique to recoup the lost funding by adding to the premium costs of midlevel silver plans in the health exchanges.

Because the formula for federal premium subsidies offered to people who purchase through the marketplaces is based on the prices of those silver plans, as those premiums rose so did the subsidies to help people afford them. That meant the federal government ended up paying much of the increase in prices.

At the committee hearing June 6, under questioning from Rep. Joe Courtney (D-Conn.), Mr. Azar declined to say if the department was considering a future ban.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

For people with diabetes, disease management can become a part-time job that affects their actual jobs, their sleep, their relationships, and their recreational activities, according to a new survey by prescription manager UpWell Health.

The time spent on activities that come with diabetes management – blood glucose monitoring, diet planning, medical appointments – can add up to several hours a week. Among the 5,255 respondents to the online survey, 18% said that such tasks took up 5-10 hours each week, 7% said it was 10-15 hours, and 9% said they spent 15 or more hours a week on diabetes-related tasks, UpWell reported.

rfranki@mdedge.com

For people with diabetes, disease management can become a part-time job that affects their actual jobs, their sleep, their relationships, and their recreational activities, according to a new survey by prescription manager UpWell Health.

The time spent on activities that come with diabetes management – blood glucose monitoring, diet planning, medical appointments – can add up to several hours a week. Among the 5,255 respondents to the online survey, 18% said that such tasks took up 5-10 hours each week, 7% said it was 10-15 hours, and 9% said they spent 15 or more hours a week on diabetes-related tasks, UpWell reported.

rfranki@mdedge.com

For people with diabetes, disease management can become a part-time job that affects their actual jobs, their sleep, their relationships, and their recreational activities, according to a new survey by prescription manager UpWell Health.

The time spent on activities that come with diabetes management – blood glucose monitoring, diet planning, medical appointments – can add up to several hours a week. Among the 5,255 respondents to the online survey, 18% said that such tasks took up 5-10 hours each week, 7% said it was 10-15 hours, and 9% said they spent 15 or more hours a week on diabetes-related tasks, UpWell reported.

rfranki@mdedge.com

In the United States, family physicians (general practitioners) used to manage their patients in the hospital, either as the primary care doctor or in consultation with specialists. Only since the 1990s has a new kind of physician gained widespread acceptance: the hospitalist (“specialist of inpatient care”).¹

In Italy the process has not been the same. In our health care system, primary care physicians have always transferred the responsibility of hospital care to an inpatient team. Actually, our hospital-based doctors dedicate their whole working time to inpatient care, and general practitioners are not expected to go to the hospital. The patients were (and are) admitted to one ward or another according to their main clinical problem.

Little by little, a huge number of organ specialty and subspecialty wards have filled Italian hospitals. In this context, the internal medicine specialty was unable to occupy its characteristic role, so that, a few years ago, the medical community wondered if the specialty should have continued to exist.

References

1. Baudendistel TE, Watcher RM. The evolution of the hospitalist movement in USA. Clin Med JRCPL. 2002;2:327-30.

2. Pantilat S. What is a Hospitalist? The Hospitalist 2006 February;2006(2).

3. Wachter RM, Goldman Lee. The emerging role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335:514-7.

4. White HL, Glazier RH. Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. BMC Medicine. 2011;9:58:1-22. http://www.biomedcentral.com/1741-7015/9/58.

5. Wachter RM, Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016;375:1009-11.
 

Valerio Verdiani, MD, director of internal medicine, Grosseto, Italy. Francesco Orlandini, MD, internal medicine, health administrator, ASL4 Liguria, Chiavari (GE), Italy. Micaela La Regina, MD, internal medicine, risk management and clinical governance, ASL5 Liguria, La Spezia, Italy. Giovanni Murialdo, MD, department of internal medicine and medical specialty, University of Genoa (Italy). Andrea Fontanella, MD, director of medicine department, president of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), Naples, Italy. Mauro Silingardi, MD, director of internal medicine, director of training and refresher of FADOI, Bologna, Italy.

In the United States, family physicians (general practitioners) used to manage their patients in the hospital, either as the primary care doctor or in consultation with specialists. Only since the 1990s has a new kind of physician gained widespread acceptance: the hospitalist (“specialist of inpatient care”).¹

In Italy the process has not been the same. In our health care system, primary care physicians have always transferred the responsibility of hospital care to an inpatient team. Actually, our hospital-based doctors dedicate their whole working time to inpatient care, and general practitioners are not expected to go to the hospital. The patients were (and are) admitted to one ward or another according to their main clinical problem.

Little by little, a huge number of organ specialty and subspecialty wards have filled Italian hospitals. In this context, the internal medicine specialty was unable to occupy its characteristic role, so that, a few years ago, the medical community wondered if the specialty should have continued to exist.

References

1. Baudendistel TE, Watcher RM. The evolution of the hospitalist movement in USA. Clin Med JRCPL. 2002;2:327-30.

2. Pantilat S. What is a Hospitalist? The Hospitalist 2006 February;2006(2).

3. Wachter RM, Goldman Lee. The emerging role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335:514-7.

4. White HL, Glazier RH. Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. BMC Medicine. 2011;9:58:1-22. http://www.biomedcentral.com/1741-7015/9/58.

5. Wachter RM, Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016;375:1009-11.
 

Valerio Verdiani, MD, director of internal medicine, Grosseto, Italy. Francesco Orlandini, MD, internal medicine, health administrator, ASL4 Liguria, Chiavari (GE), Italy. Micaela La Regina, MD, internal medicine, risk management and clinical governance, ASL5 Liguria, La Spezia, Italy. Giovanni Murialdo, MD, department of internal medicine and medical specialty, University of Genoa (Italy). Andrea Fontanella, MD, director of medicine department, president of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), Naples, Italy. Mauro Silingardi, MD, director of internal medicine, director of training and refresher of FADOI, Bologna, Italy.

In the United States, family physicians (general practitioners) used to manage their patients in the hospital, either as the primary care doctor or in consultation with specialists. Only since the 1990s has a new kind of physician gained widespread acceptance: the hospitalist (“specialist of inpatient care”).¹

In Italy the process has not been the same. In our health care system, primary care physicians have always transferred the responsibility of hospital care to an inpatient team. Actually, our hospital-based doctors dedicate their whole working time to inpatient care, and general practitioners are not expected to go to the hospital. The patients were (and are) admitted to one ward or another according to their main clinical problem.

Little by little, a huge number of organ specialty and subspecialty wards have filled Italian hospitals. In this context, the internal medicine specialty was unable to occupy its characteristic role, so that, a few years ago, the medical community wondered if the specialty should have continued to exist.

References

1. Baudendistel TE, Watcher RM. The evolution of the hospitalist movement in USA. Clin Med JRCPL. 2002;2:327-30.

2. Pantilat S. What is a Hospitalist? The Hospitalist 2006 February;2006(2).

3. Wachter RM, Goldman Lee. The emerging role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335:514-7.

4. White HL, Glazier RH. Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. BMC Medicine. 2011;9:58:1-22. http://www.biomedcentral.com/1741-7015/9/58.

5. Wachter RM, Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016;375:1009-11.
 

Valerio Verdiani, MD, director of internal medicine, Grosseto, Italy. Francesco Orlandini, MD, internal medicine, health administrator, ASL4 Liguria, Chiavari (GE), Italy. Micaela La Regina, MD, internal medicine, risk management and clinical governance, ASL5 Liguria, La Spezia, Italy. Giovanni Murialdo, MD, department of internal medicine and medical specialty, University of Genoa (Italy). Andrea Fontanella, MD, director of medicine department, president of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), Naples, Italy. Mauro Silingardi, MD, director of internal medicine, director of training and refresher of FADOI, Bologna, Italy.

The American Society of Hematology (ASH) has released a new policy statement in favor of safeguarding access to opioids for hematology patients with chronic, severe pain as policymakers consider restrictions on opioid prescribing.

The statement is a recognition from ASH officials of the large number of opioid overdose deaths that involve prescription medication, and an acknowledgment that hematologists need to be advocates for their patients, said Joseph Alvarnas, MD, of City of Hope, Duarte, Calif.

Courtesy of City of Hope

In a rule finalized in April 2018, the CMS placed restrictions on the dosage of opioids available for chronic opioid users and limited the days’ supply for first-time opioid users. For chronic users, the CMS set a 90-morphine-milligram-equivalent (MME) per day limit that triggers pharmacist consultation with the prescriber. The agency instructed health plans to implement an “opioid care coordination edit” that would be triggered at 90 MME per day across all opioid prescriptions and would require pharmacists to contact prescribers to override for a higher dosage.

The entire exchange must be documented. The CMS instructed health plans in the Medicare Part D program to implement a “hard safety edit” that limits opioid prescription fills to no more than a 7-day supply for opioid-naive patients being treated for acute pain. The changes are set to take effect in January 2019.

But Diane E. Meier, MD, director of the Center to Advance Palliative Care in New York, said the most current data suggest the risk of addiction and substance use disorder among medically-ill patients taking opioids is less than 10%. “That means that 90% of patients with a serious medical illness can safely take opioids for the relief of pain that is causing functional disorder,” she said.

Policymakers should not conflate the use and prescription of opioids with cases of misuse and abuse, Dr. Alvarnas said. Some patients will require a higher dose of opioids depending on their age or number of pain episodes, or because of their body’s physiological response.

Patients may also have difficulty finding pharmacies that dispense opioid medications, or doctors who will prescribe them, because of fear of repercussions from the Drug Enforcement Administration or their state licensing boards, Dr. Meier said.

No ‘one-size-fits-all’

Because treatment is individualized, there is no “one-size-fits-all” approach to pain management for patients with hematological diseases.

“One of the concerns is that we care for populations of patients, such as those with sickle cell disease, those with blood cancers that can cause destructive bony lesions like somebody with multiple myeloma might experience, or even pain associated with the complication of a disease like hemophilia, where [patients experience] excruciating pain ... from bleeding into a joint,” Dr. Alvarnas said.

It’s not enough to offer anti-inflammatory medications to these patients – and in some cases doing so may create additional problems, experts said. Contraindications for anti-inflammatory agents tend to be more significant in hematology patients because of low platelet counts, liver disease, and kidney disease. This may prevent them from taking medications such as ibuprofen, acetaminophen, or naproxen sodium. Opioids are the “only option” for patients with these kinds of complications who have severe pain, Dr. Osunkwo said.
 

Pain management training

While hematologists are trained about the potential risks of common drugs such as steroids, “none of that education and training has occurred” for opioids, Dr. Meier said.

Finding balance

ASH leaders recognize the longstanding, complex nature of the opioid epidemic and want to be a part of the conversation to ensure their patients’ needs and considerations are met in future legislation, Dr. Alvarnas noted.

Dr. Meier, who is vice chair for public policy at Icahn School of Medicine at Mount Sinai, New York, said the issue of balance is paramount when considering good policymaking.

“No policy at either extreme is the right policy,” Dr. Meier said. “Good policymaking, good public health interventions attempt to achieve some balance ... in preventing harm and maximizing appropriate treatment of vulnerable, seriously ill patients. And the policies we have now don’t achieve that.”

The “Statement on Opioid Use in Patients with Hematologic Diseases and Disorders” is available on the ASH website.

Dr. Alvarnas is chair of the society’s Committee on Practice. Dr. Meier and Dr. Osunkwo reported having no relevant financial disclosures.

The American Society of Hematology (ASH) has released a new policy statement in favor of safeguarding access to opioids for hematology patients with chronic, severe pain as policymakers consider restrictions on opioid prescribing.

The statement is a recognition from ASH officials of the large number of opioid overdose deaths that involve prescription medication, and an acknowledgment that hematologists need to be advocates for their patients, said Joseph Alvarnas, MD, of City of Hope, Duarte, Calif.

Courtesy of City of Hope

In a rule finalized in April 2018, the CMS placed restrictions on the dosage of opioids available for chronic opioid users and limited the days’ supply for first-time opioid users. For chronic users, the CMS set a 90-morphine-milligram-equivalent (MME) per day limit that triggers pharmacist consultation with the prescriber. The agency instructed health plans to implement an “opioid care coordination edit” that would be triggered at 90 MME per day across all opioid prescriptions and would require pharmacists to contact prescribers to override for a higher dosage.

The entire exchange must be documented. The CMS instructed health plans in the Medicare Part D program to implement a “hard safety edit” that limits opioid prescription fills to no more than a 7-day supply for opioid-naive patients being treated for acute pain. The changes are set to take effect in January 2019.

But Diane E. Meier, MD, director of the Center to Advance Palliative Care in New York, said the most current data suggest the risk of addiction and substance use disorder among medically-ill patients taking opioids is less than 10%. “That means that 90% of patients with a serious medical illness can safely take opioids for the relief of pain that is causing functional disorder,” she said.

Policymakers should not conflate the use and prescription of opioids with cases of misuse and abuse, Dr. Alvarnas said. Some patients will require a higher dose of opioids depending on their age or number of pain episodes, or because of their body’s physiological response.

Patients may also have difficulty finding pharmacies that dispense opioid medications, or doctors who will prescribe them, because of fear of repercussions from the Drug Enforcement Administration or their state licensing boards, Dr. Meier said.

No ‘one-size-fits-all’

Because treatment is individualized, there is no “one-size-fits-all” approach to pain management for patients with hematological diseases.

“One of the concerns is that we care for populations of patients, such as those with sickle cell disease, those with blood cancers that can cause destructive bony lesions like somebody with multiple myeloma might experience, or even pain associated with the complication of a disease like hemophilia, where [patients experience] excruciating pain ... from bleeding into a joint,” Dr. Alvarnas said.

It’s not enough to offer anti-inflammatory medications to these patients – and in some cases doing so may create additional problems, experts said. Contraindications for anti-inflammatory agents tend to be more significant in hematology patients because of low platelet counts, liver disease, and kidney disease. This may prevent them from taking medications such as ibuprofen, acetaminophen, or naproxen sodium. Opioids are the “only option” for patients with these kinds of complications who have severe pain, Dr. Osunkwo said.
 

Pain management training

While hematologists are trained about the potential risks of common drugs such as steroids, “none of that education and training has occurred” for opioids, Dr. Meier said.

Finding balance

ASH leaders recognize the longstanding, complex nature of the opioid epidemic and want to be a part of the conversation to ensure their patients’ needs and considerations are met in future legislation, Dr. Alvarnas noted.

Dr. Meier, who is vice chair for public policy at Icahn School of Medicine at Mount Sinai, New York, said the issue of balance is paramount when considering good policymaking.

“No policy at either extreme is the right policy,” Dr. Meier said. “Good policymaking, good public health interventions attempt to achieve some balance ... in preventing harm and maximizing appropriate treatment of vulnerable, seriously ill patients. And the policies we have now don’t achieve that.”

The “Statement on Opioid Use in Patients with Hematologic Diseases and Disorders” is available on the ASH website.

Dr. Alvarnas is chair of the society’s Committee on Practice. Dr. Meier and Dr. Osunkwo reported having no relevant financial disclosures.

The American Society of Hematology (ASH) has released a new policy statement in favor of safeguarding access to opioids for hematology patients with chronic, severe pain as policymakers consider restrictions on opioid prescribing.

The statement is a recognition from ASH officials of the large number of opioid overdose deaths that involve prescription medication, and an acknowledgment that hematologists need to be advocates for their patients, said Joseph Alvarnas, MD, of City of Hope, Duarte, Calif.

Courtesy of City of Hope

In a rule finalized in April 2018, the CMS placed restrictions on the dosage of opioids available for chronic opioid users and limited the days’ supply for first-time opioid users. For chronic users, the CMS set a 90-morphine-milligram-equivalent (MME) per day limit that triggers pharmacist consultation with the prescriber. The agency instructed health plans to implement an “opioid care coordination edit” that would be triggered at 90 MME per day across all opioid prescriptions and would require pharmacists to contact prescribers to override for a higher dosage.

The entire exchange must be documented. The CMS instructed health plans in the Medicare Part D program to implement a “hard safety edit” that limits opioid prescription fills to no more than a 7-day supply for opioid-naive patients being treated for acute pain. The changes are set to take effect in January 2019.

But Diane E. Meier, MD, director of the Center to Advance Palliative Care in New York, said the most current data suggest the risk of addiction and substance use disorder among medically-ill patients taking opioids is less than 10%. “That means that 90% of patients with a serious medical illness can safely take opioids for the relief of pain that is causing functional disorder,” she said.

Policymakers should not conflate the use and prescription of opioids with cases of misuse and abuse, Dr. Alvarnas said. Some patients will require a higher dose of opioids depending on their age or number of pain episodes, or because of their body’s physiological response.

Patients may also have difficulty finding pharmacies that dispense opioid medications, or doctors who will prescribe them, because of fear of repercussions from the Drug Enforcement Administration or their state licensing boards, Dr. Meier said.

No ‘one-size-fits-all’

Because treatment is individualized, there is no “one-size-fits-all” approach to pain management for patients with hematological diseases.

“One of the concerns is that we care for populations of patients, such as those with sickle cell disease, those with blood cancers that can cause destructive bony lesions like somebody with multiple myeloma might experience, or even pain associated with the complication of a disease like hemophilia, where [patients experience] excruciating pain ... from bleeding into a joint,” Dr. Alvarnas said.

It’s not enough to offer anti-inflammatory medications to these patients – and in some cases doing so may create additional problems, experts said. Contraindications for anti-inflammatory agents tend to be more significant in hematology patients because of low platelet counts, liver disease, and kidney disease. This may prevent them from taking medications such as ibuprofen, acetaminophen, or naproxen sodium. Opioids are the “only option” for patients with these kinds of complications who have severe pain, Dr. Osunkwo said.
 

Pain management training

While hematologists are trained about the potential risks of common drugs such as steroids, “none of that education and training has occurred” for opioids, Dr. Meier said.

Finding balance

ASH leaders recognize the longstanding, complex nature of the opioid epidemic and want to be a part of the conversation to ensure their patients’ needs and considerations are met in future legislation, Dr. Alvarnas noted.

Dr. Meier, who is vice chair for public policy at Icahn School of Medicine at Mount Sinai, New York, said the issue of balance is paramount when considering good policymaking.

“No policy at either extreme is the right policy,” Dr. Meier said. “Good policymaking, good public health interventions attempt to achieve some balance ... in preventing harm and maximizing appropriate treatment of vulnerable, seriously ill patients. And the policies we have now don’t achieve that.”

The “Statement on Opioid Use in Patients with Hematologic Diseases and Disorders” is available on the ASH website.

Dr. Alvarnas is chair of the society’s Committee on Practice. Dr. Meier and Dr. Osunkwo reported having no relevant financial disclosures.

ORLANDO – Although cardiologists and neurologists aren’t typically the physicians who diagnose and treat major depressive disorder that’s newly identified in patients after MI or stroke, they’re the ones who’ll deal with the cardiovascular consequences if the mood disorder isn’t adequately treated.

That was a key message of a study presented by interventional cardiologist Sripal Bangalore, MD, at the annual meeting of the American College of Cardiology.

In his retrospective cohort study of 1,568 patients diagnosed with and treated for major depressive disorder (MDD) following an initial acute MI or stroke, antidepressant therapy deemed inadequate by either of two prespecified measures was associated during a mean follow-up of 2 years with a 20% higher risk of the primary endpoint – a composite of recurrent MI, stroke, angina, or heart failure – than the risk in patients who received what was judged to be adequate antidepressant pharmacotherapy. A precondition for study inclusion was that a patient could not have been taking any antidepressant during the year prior to the index MI or stroke.

The study utilized nationwide claims data from the Truven Health MarketScan Claims Database for 2010-2015. Depression therapy was considered adequate if during the first 90 days following diagnosis of MDD two conditions were met: a patient aged 65 or younger had to be on the equivalent of at least 20 mg of fluoxetine per day, or if older then on a fluoxetine-equivalent dose of at least 10 mg/day, and pharmacy records had to indicate the patient was covered by the antidepressant prescription for at least 72 of those 90 days.

The prevalence of inadequate antidepressant therapy for MDD by these criteria among these patients with known cardiovascular disease was eyebrow-raisingly high: fully 60%, noted Dr. Bangalore of New York University.

In a multivariate logistic regression analysis adjusted for baseline factors that could affect the propensity to receive adequate antidepressant care, Dr. Bangalore and his coinvestigators broke down the risks of insufficient antidepressant therapy associated with each of the individual components of the composite primary endpoint. The 1.2- and 1.95-fold increased risks of stroke and angina, respectively, were statistically significant. However, the 1.37-fold higher risk of MI and 1.14-fold greater risk of heart failure than in adequately treated patients with MDD, while trending in the same direction, didn’t achieve significance.

Dr. Bangalore reported serving as a consultant to Pfizer, which funded the study, as well as to Abbott, Gilead Sciences, and Merck.

bjancin@mdedge.com

ORLANDO – Although cardiologists and neurologists aren’t typically the physicians who diagnose and treat major depressive disorder that’s newly identified in patients after MI or stroke, they’re the ones who’ll deal with the cardiovascular consequences if the mood disorder isn’t adequately treated.

That was a key message of a study presented by interventional cardiologist Sripal Bangalore, MD, at the annual meeting of the American College of Cardiology.

In his retrospective cohort study of 1,568 patients diagnosed with and treated for major depressive disorder (MDD) following an initial acute MI or stroke, antidepressant therapy deemed inadequate by either of two prespecified measures was associated during a mean follow-up of 2 years with a 20% higher risk of the primary endpoint – a composite of recurrent MI, stroke, angina, or heart failure – than the risk in patients who received what was judged to be adequate antidepressant pharmacotherapy. A precondition for study inclusion was that a patient could not have been taking any antidepressant during the year prior to the index MI or stroke.

The study utilized nationwide claims data from the Truven Health MarketScan Claims Database for 2010-2015. Depression therapy was considered adequate if during the first 90 days following diagnosis of MDD two conditions were met: a patient aged 65 or younger had to be on the equivalent of at least 20 mg of fluoxetine per day, or if older then on a fluoxetine-equivalent dose of at least 10 mg/day, and pharmacy records had to indicate the patient was covered by the antidepressant prescription for at least 72 of those 90 days.

The prevalence of inadequate antidepressant therapy for MDD by these criteria among these patients with known cardiovascular disease was eyebrow-raisingly high: fully 60%, noted Dr. Bangalore of New York University.

In a multivariate logistic regression analysis adjusted for baseline factors that could affect the propensity to receive adequate antidepressant care, Dr. Bangalore and his coinvestigators broke down the risks of insufficient antidepressant therapy associated with each of the individual components of the composite primary endpoint. The 1.2- and 1.95-fold increased risks of stroke and angina, respectively, were statistically significant. However, the 1.37-fold higher risk of MI and 1.14-fold greater risk of heart failure than in adequately treated patients with MDD, while trending in the same direction, didn’t achieve significance.

Dr. Bangalore reported serving as a consultant to Pfizer, which funded the study, as well as to Abbott, Gilead Sciences, and Merck.

bjancin@mdedge.com

ORLANDO – Although cardiologists and neurologists aren’t typically the physicians who diagnose and treat major depressive disorder that’s newly identified in patients after MI or stroke, they’re the ones who’ll deal with the cardiovascular consequences if the mood disorder isn’t adequately treated.

That was a key message of a study presented by interventional cardiologist Sripal Bangalore, MD, at the annual meeting of the American College of Cardiology.

In his retrospective cohort study of 1,568 patients diagnosed with and treated for major depressive disorder (MDD) following an initial acute MI or stroke, antidepressant therapy deemed inadequate by either of two prespecified measures was associated during a mean follow-up of 2 years with a 20% higher risk of the primary endpoint – a composite of recurrent MI, stroke, angina, or heart failure – than the risk in patients who received what was judged to be adequate antidepressant pharmacotherapy. A precondition for study inclusion was that a patient could not have been taking any antidepressant during the year prior to the index MI or stroke.

The study utilized nationwide claims data from the Truven Health MarketScan Claims Database for 2010-2015. Depression therapy was considered adequate if during the first 90 days following diagnosis of MDD two conditions were met: a patient aged 65 or younger had to be on the equivalent of at least 20 mg of fluoxetine per day, or if older then on a fluoxetine-equivalent dose of at least 10 mg/day, and pharmacy records had to indicate the patient was covered by the antidepressant prescription for at least 72 of those 90 days.

The prevalence of inadequate antidepressant therapy for MDD by these criteria among these patients with known cardiovascular disease was eyebrow-raisingly high: fully 60%, noted Dr. Bangalore of New York University.

In a multivariate logistic regression analysis adjusted for baseline factors that could affect the propensity to receive adequate antidepressant care, Dr. Bangalore and his coinvestigators broke down the risks of insufficient antidepressant therapy associated with each of the individual components of the composite primary endpoint. The 1.2- and 1.95-fold increased risks of stroke and angina, respectively, were statistically significant. However, the 1.37-fold higher risk of MI and 1.14-fold greater risk of heart failure than in adequately treated patients with MDD, while trending in the same direction, didn’t achieve significance.

Dr. Bangalore reported serving as a consultant to Pfizer, which funded the study, as well as to Abbott, Gilead Sciences, and Merck.

bjancin@mdedge.com

WASHINGTON – Hospitalizations for shingles is twice as common among patients with inflammatory bowel disease than in the general U.S. population, based on analysis of data from the National Inpatient Sample.

Mitchel L. Zoler/MDedge News

This elevated risk for patients with inflammatory bowel disease (IBD) to develop a herpes zoster virus (HZV) reactivation severe enough to put them in the hospital makes it especially important for IBD patients to receive immunization against shingles, especially now that a more effective vaccine is available, Daniela G. Vinsard, MD, said at the annual Digestive Disease Week^®. Ideally, IBD patients should receive the full course of the adjuvanted, recombinant zoster vaccine Shingrix before starting an immunosuppressive regimen, said Dr. Vinsard, a physician at the University of Connecticut, Farmington.

This finding, which underscored the susceptibility of IBD patients to shingles because of their immunosuppressive treatments and the importance of vaccination, recently became even more relevant when the Food and Drug Administration approved tofacitinib (Xeljanz) to treat ulcerative colitis in late May, commented Gil Y. Melmed, MD, director of clinical inflammatory bowel disease at Cedars-Sinai Medical Center, Los Angeles. Tofacitinib, which may be an attractive option to some patients as an oral immunomodulator, carries a black box warning about the added risk for certain serious infections while taking the drug, including HZV. Recent recommendations from the American College of Gastroenterology said that IBD patients aged 51 years or older should “strongly consider” HZV vaccination, including immunosuppressed patients (Am J Gastroenterol. 2017 Feb; 112[2]:241-58). The introduction of a potentially popular drug for ulcerative colitis that’s known to pose a risk for shingles might lead to a stronger recommendation for vaccination in the near future, Dr. Melmed said in an interview.

The study Dr. Vinsard reported used data collected by the National Inpatient Sample from 2012 to September 2015, which represented, with weighting, more than 142 million hospitalized American patients. From this data set she and her associates identified 7,180 IBD patients hospitalized with a primary diagnosis of a vaccine-preventable disease, and about 589,000 weighted patients hospitalized for a vaccine-preventable disease but without IBD. The selection also focused on patients aged 18-65 years. Dr. Vinsard said that she excluded older patients to eliminate advanced age as a cause of immunosuppression.

mzoler@mdedge.com

WASHINGTON – Hospitalizations for shingles is twice as common among patients with inflammatory bowel disease than in the general U.S. population, based on analysis of data from the National Inpatient Sample.

Mitchel L. Zoler/MDedge News

This elevated risk for patients with inflammatory bowel disease (IBD) to develop a herpes zoster virus (HZV) reactivation severe enough to put them in the hospital makes it especially important for IBD patients to receive immunization against shingles, especially now that a more effective vaccine is available, Daniela G. Vinsard, MD, said at the annual Digestive Disease Week^®. Ideally, IBD patients should receive the full course of the adjuvanted, recombinant zoster vaccine Shingrix before starting an immunosuppressive regimen, said Dr. Vinsard, a physician at the University of Connecticut, Farmington.

This finding, which underscored the susceptibility of IBD patients to shingles because of their immunosuppressive treatments and the importance of vaccination, recently became even more relevant when the Food and Drug Administration approved tofacitinib (Xeljanz) to treat ulcerative colitis in late May, commented Gil Y. Melmed, MD, director of clinical inflammatory bowel disease at Cedars-Sinai Medical Center, Los Angeles. Tofacitinib, which may be an attractive option to some patients as an oral immunomodulator, carries a black box warning about the added risk for certain serious infections while taking the drug, including HZV. Recent recommendations from the American College of Gastroenterology said that IBD patients aged 51 years or older should “strongly consider” HZV vaccination, including immunosuppressed patients (Am J Gastroenterol. 2017 Feb; 112[2]:241-58). The introduction of a potentially popular drug for ulcerative colitis that’s known to pose a risk for shingles might lead to a stronger recommendation for vaccination in the near future, Dr. Melmed said in an interview.

The study Dr. Vinsard reported used data collected by the National Inpatient Sample from 2012 to September 2015, which represented, with weighting, more than 142 million hospitalized American patients. From this data set she and her associates identified 7,180 IBD patients hospitalized with a primary diagnosis of a vaccine-preventable disease, and about 589,000 weighted patients hospitalized for a vaccine-preventable disease but without IBD. The selection also focused on patients aged 18-65 years. Dr. Vinsard said that she excluded older patients to eliminate advanced age as a cause of immunosuppression.

mzoler@mdedge.com

WASHINGTON – Hospitalizations for shingles is twice as common among patients with inflammatory bowel disease than in the general U.S. population, based on analysis of data from the National Inpatient Sample.

Mitchel L. Zoler/MDedge News

This elevated risk for patients with inflammatory bowel disease (IBD) to develop a herpes zoster virus (HZV) reactivation severe enough to put them in the hospital makes it especially important for IBD patients to receive immunization against shingles, especially now that a more effective vaccine is available, Daniela G. Vinsard, MD, said at the annual Digestive Disease Week^®. Ideally, IBD patients should receive the full course of the adjuvanted, recombinant zoster vaccine Shingrix before starting an immunosuppressive regimen, said Dr. Vinsard, a physician at the University of Connecticut, Farmington.

This finding, which underscored the susceptibility of IBD patients to shingles because of their immunosuppressive treatments and the importance of vaccination, recently became even more relevant when the Food and Drug Administration approved tofacitinib (Xeljanz) to treat ulcerative colitis in late May, commented Gil Y. Melmed, MD, director of clinical inflammatory bowel disease at Cedars-Sinai Medical Center, Los Angeles. Tofacitinib, which may be an attractive option to some patients as an oral immunomodulator, carries a black box warning about the added risk for certain serious infections while taking the drug, including HZV. Recent recommendations from the American College of Gastroenterology said that IBD patients aged 51 years or older should “strongly consider” HZV vaccination, including immunosuppressed patients (Am J Gastroenterol. 2017 Feb; 112[2]:241-58). The introduction of a potentially popular drug for ulcerative colitis that’s known to pose a risk for shingles might lead to a stronger recommendation for vaccination in the near future, Dr. Melmed said in an interview.

The study Dr. Vinsard reported used data collected by the National Inpatient Sample from 2012 to September 2015, which represented, with weighting, more than 142 million hospitalized American patients. From this data set she and her associates identified 7,180 IBD patients hospitalized with a primary diagnosis of a vaccine-preventable disease, and about 589,000 weighted patients hospitalized for a vaccine-preventable disease but without IBD. The selection also focused on patients aged 18-65 years. Dr. Vinsard said that she excluded older patients to eliminate advanced age as a cause of immunosuppression.

mzoler@mdedge.com

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.

In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.

Neil Osterweil/MDedge News

In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.

“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
 

Synergism sought

The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.

Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.

Two groups, two TKIs, one PD-L1 inhibitor

Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.

Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.

In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.

There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.

Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.

In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.

Antitumor activity

In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.

In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.

“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.

Neil Osterweil/MDedge News

But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.

“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.

She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.

“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.

The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”

In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.

“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.

She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.

SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.

CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.

In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.

Neil Osterweil/MDedge News

In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.

“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
 

Synergism sought

The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.

Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.

Two groups, two TKIs, one PD-L1 inhibitor

Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.

Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.

In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.

There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.

Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.

In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.

Antitumor activity

In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.

In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.

“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.

Neil Osterweil/MDedge News

But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.

“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.

She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.

“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.

The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”

In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.

“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.

She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.

SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.

CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.

In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.

Neil Osterweil/MDedge News

In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.

“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
 

Synergism sought

The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.

Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.

Two groups, two TKIs, one PD-L1 inhibitor

Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.

Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.

In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.

There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.

Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.

In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.

Antitumor activity

In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.

In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.

“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.

Neil Osterweil/MDedge News

But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.

“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.

She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.

“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.

The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”

In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.

“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.

She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.

SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.